ABSTRACT Oral mucositis is a devastatingly painful inflammatory disease that frequently develops during cancer therapy and affects half a million people in the US. The accompanying pain is so severe that patients often require narcotic pain medicines. The clinical manifestations are ulcers in the mouth and gastrointestinal tract, which are exacerbated by opportunistic infections. Many patients also suffer from dry mouth causing difficulty in swallowing because of the decreased salivary gland function. As a result, these patients often need feeding tubes which interrupts their cancer treatment. The financial burden to the patient is staggeringly high costing an additional $17,000 to $40,000 for each patient. Preventing oral mucositis will therefore greatly enhance the cancer therapy as well as the wellness of the patients. GlycoMira's lead candidate, GM-0111, is a new class of anti-inflammatory drugs. The SBIR Phase I study results demonstrate its powerful anti-inflammatory effects in a radiation-induced oral mucositis animal model: GM-0111 reduced tissue ulceration and inflammation in the tongue. Histologically, tongue tissues from the GM-0111 treated group showed markedly reduced infiltration of leukocytes with thicker mucosal layers and prevention of mucous glandular alterations compared to the tissues from vehicle treated animals. Biochemical analyses also showed consistently lower leukocyte enzyme MPO activity as well as reduced concentration of nerve growth factor (NGF) in GM-0111 treatment groups. In addition, GM-0111 treatment prevented radiation-induced alterations of the salivary glands. Overall, the data suggest that it is feasible to use GM-0111 to prevent oral mucositis. The current SBIR Phase II application proposes to further develop GM-0111 as a viable and effective therapy for oral mucositis. The objectives are to (1) investigate the optimal dosing regimen in a radiation-induced oral mucositis animal model, (2) determine the optimal formulation for topical delivery of GM-0111 in the oral mucosa, (3) validate the topical GM-0111 formulation in radiation and chemoradiation-induced animal models, and (4) investigate the molecular targets of GM-0111 to reduce oral mucositis. The results of the proposed research will lead to the delivery of a viable and effective therapy to the patients suffering from this devastating disease.